1. Dallas 2015 TFQO: Monica Kleinman COI #353 EVREV 1: Janice Tijssen COI#232 EVREV 2: Javier Urbano COI#240 Taskforce: Peds Peds 815: Pediatric goal-directed ventilation post-ROSC

2. Dallas 2015 COI Disclosure (specific to this systematic review) Janice Tijssen COI#232 Commercial/industry None Potential intellectual conflicts None Javier Urbano COI#240 Commercial/industry None Potential intellectual conflicts None

3. Dallas 2015 2010 CoSTR Adults: After restoration of circulation, routine hyperventilation leading to hypocapnia should be avoided to prevent additional cerebral ischemia Pediatrics: No post-resuscitation care guidelines for ventilation exist

4. Dallas 2015 C2015 PICO Population: Infants and children with ROSC after cardiac arrest in any setting Intervention: Ventilation to a specific PCO2 target Comparison: Ventilation to no specific PC02 target Outcomes Critical: Survival with favorable neurologic outcome, survival to 180/30 days with good neurologic outcome, hospital discharge, the likelihood of a good quality of life after discharge from the hospital Important: Survival to 6 months, 60/30 days, hospital discharge, ICU discharge.

5. Dallas 2015 Inclusion/Exclusion & Articles Found Inclusions 2 /Exclusions 998 No RCTs were identified We did not include adult or animal studies Number of Articles Finally Evaluated: 2 observational studies in children

6. Dallas 2015 2015 Proposed Treatment Recommendations We suggest maintaining pCO2 within a normal physiological range as part of a post-ROSC bundle of care (weak recommendation, very low quality evidence)

7. Dallas 2015 Risk of Bias in studies Non-RCT bias asssessment StudyYearDesign Total Patients Population Industry Funding Eligibility Criteria Exposure/Outcome Confounding Follow up Del Castillo 2012 Prospective observational 221 Pediatric (1mo-18y), IHCA only 2 non- industry grants unclear high unclear Bennett 2013 Retrospective observational 195 24h to 18y, IHCA and OHCA Grant supported lowhighlow

8. Dallas 2015 Key data from key studies Reference: Del Castillo J, 2012, 1456. P: 223 patients (1m-18y) with in-hospital cardiac arrest I: Prospective, observational C: Normocapnia (30-50 mmHg) vs. Hyper- or Hypocapnia O: Blood gas at ROSC: After multivariate regression, the OR of mortality for: Hypercapnia (3.27; 95% CI, 1.62-6.61; p=0.001) and Hypocapnia (2.71; 95% CI, 1.04-7.05; p=0.04) Blood gas at 24h: No difference in mortality (not adjusted) for hypo and hypercapnia

9. Dallas 2015 Key data from key studies Reference: Bennett KS, 2013, 1534. P: 195 patients (24h-18y) with both in and out-of-hospital cardiac arrest I: Retrospective, observational (minimum and maximum blood gas values recorded in first 6 hours) C: Normocapnia (30-50 mmHg) vs. Hyper- or Hypocapnia O: Ventilation status was not associated with favourable neurological outcome (PCPC 1-2) at hospital discharge.

10. Dallas 2015 Normo vs Hypercapnia Author(s) : Janice Tijssen, Javier Urbano Date : 20 Jan 2015 Question : Ventilation adjusted to normocapnia compared to ventilation adjusted to hypercapnia for improvement of neurological outcome after ROSC in pediatric patients Settings : Cardiac arrests Bibliography (systematic reviews) : 1.. Del Castillo, Resuscitation, 2012 2. Bennett, CCM, 2013. Quality assessment№ of patientsEffect QualityImportance № of studies Study design Risk of bias Inconsisten cy IndirectnessImprecision Other considerati ons ventilation to hypercapnia normocapni a Relative (95% CI) Absolute (95% CI) Survival with Favorable neurological/functional outcome at discharge in pediatric patients (assessed with: PCPC 1-2 or no change with baseline pre-CA) 1 observationa l studies serious 7 not seriousserious 1 serious 2 none 23/64 (35.9%) 27/57 (47.4%) RR 0.7587 (0.4953 to 1.1622) 114 fewer per 1000 (from 77 more to 239 fewer) 8 ⨁ ◯◯◯ VERY LOW CRITICAL Survival to hospital discharge in pediatric patients 1observationa l studies serious 3 serious 4 serious 1 5 serious 6 none8/25 (32.0%)79/118 (66.9%) RR 0.478 (0.2662 to 0.8582) 349 fewer per 1000 (from 95 fewer to 491 fewer) ⨁ ◯◯◯ VERY LOW IMPORTANT

11. Dallas 2015 Normo vs Hypocapnia Author(s) : Janice Tijssen, Javier Urbano Date : 20 Jan 2015 Question : Ventilation adjusted to normocapnia compared to ventilation adjusted to hypercapnia for improvement of neurological outcome after ROSC in pediatric patients Settings : Cardiac arrests Bibliography (systematic reviews) : 1.. Del Castillo, Resuscitation, 2012 2. Bennett, CCM, 2013. Quality assessment№ of patientsEffect QualityImportance № of studies Study design Risk of bias Inconsisten cy IndirectnessImprecision Other consideratio ns ventilation to hypocapnia normocapni a Relative (95% CI) Absolute (95% CI) Survival with Favorable neurological/functional outcome at discharge in pediatric patients (assessed with: PCPC 1-2 or no change with baseline pre-CA)- Bennett, CCM, 2013 1 observationa l studies serious 1 not seriousserious 1 none 16/48 (33.3%) 27/57 (47.4%) RR 0.7037 (0.4334 to 1.1426) 140 fewer per 1000 (from 68 more to 268 fewer) 2 ⨁ ◯◯◯ VERY LOW CRITICAL Survival to hospital discharge in pediatric patients- Del Castillo, Resuscitation, 2012 1observationa l studies very serious 3 not seriousserious 3 none5/9 (55.6%)79/118 (66.9%) RR 0.8298 (0.4563 to 1.5089) 114 fewer per 1000 (from 341 more to 364 fewer) ⨁ ◯◯◯ VERY LOW IMPORTANT

12. Dallas 2015 Proposed Consensus on Science statements Part A. Hypercapnia vs. Normocapnia For the critical outcome of survival to hospital discharge with favorable/functional neurological outcome in pediatric patients (assessed with PCPC 1-2 or no change with baseline pre-CA), we have identified very low quality evidence from one observational study [Bennett, 2013, 1534] of 195 pediatric in and out-of-hospital cardiac arrest survivors to at least 6 hours post-arrest (down-graded for indirectness, imprecision and serious risk of bias) showing no benefit of hypercapnia (>50 mmHg) (Relative Risk of survival to hospital discharge with favorable/functional neurological outcome is 0.7587, CI 0.4953 to 1.1622).

13. Dallas 2015 Proposed Consensus on Science statements Part A. Hypercapnia vs. Normocapnia For the important outcome of survival to hospital discharge in pediatric patients we have identified very low quality evidence from one observational study [Del Castillo, 2012, 1456] of 223 pediatric patients suffering an in-hospital cardiac arrest (down-graded for inconsistency, indirectness, imprecision and serious risk of bias). This study showedworse outcomewith hypercapnia(≥ 50 mmHg) (Relative Risk of survival to hospital discharge is 0.478, CI 0.2662 to 0.8582).

14. Dallas 2015 Proposed Consensus on Science statements Part B. Hypocapnia vs. Normocapnia For the critical outcome of survival to hospital discharge with favorable/functional neurological outcome in pediatric patients (assessed with PCPC 1-2 or no change with baseline pre-CA), we have identified very low quality evidence from one observational study [Bennett, 2013, 1534] of 195 pediatric in and out-of-hospital cardiac arrest survivors to at least 6 hours post-arrest (down-graded for indirectness, imprecision and serious risk of bias) showing no benefit of hypocapnia (< 30 mmHg) (Relative Risk of survival to hospital discharge with favorable/functional neurological outcome 0.7037, CI 0.4334 to 1.1426).

15. Dallas 2015 Proposed Consensus on Science statements Part B. Hypocapnia vs. Normocapnia For the important outcome of survival to hospital discharge in pediatric patients we have identified very low quality evidence from one observationalstudy [Del Castillo, 2012, 1456] of 223 pediatric suffering an in-hospital cardiac arrest(down-graded for inconsistency, indirectness, imprecision and serious risk of bias) showing no benefit of hypocapnia (<30 mmHg) (Relative Risk of survival to hospital discharge is 0.8298, CI 0.4563 to 1.5089). There were no studies available to address the remaining outcomes

16. Dallas 2015 Draft Treatment Recommendations We suggest maintaining pCO2 within a normal physiological range as part of a post-ROSC bundle of care (weak recommendation, very low quality evidence)

17. Dallas 2015 Knowledge Gaps No studies demonstrate better outcome with ventilation to a specific PCO 2 in pediatric patients with ROSC The upper and lower limits at which PCO 2 becomes harmful are unknown. Hypocapnia is associated with worse outcome in adult studies. Although mild hypercapnia may have some neuroprotective effect in adult studies, this has not been observed in the pediatric population. We do not have pediatric evidence for or against ventilation targets in patients treated with therapeutic hypothermia. For the subgroup of adult patients being treated with therapeutic hypothermia, both hypocapnia and hypercapnia were not associated with benefit. Additionally, the risk of excessive hypocapnia exists if the PaCO2 is not temperature corrected. It is not known whether patients undergoing “permissive hypercapnia” as a lung protective ventilator strategy prior to cardiac arrest may benefit from maintaining this target.

18. Dallas 2015 Next Steps